The enigmatic parietal epithelial cell is finally getting noticed: a review
2009; Elsevier BV; Volume: 76; Issue: 12 Linguagem: Inglês
10.1038/ki.2009.386
ISSN1523-1755
AutoresTakamoto Ohse, Jeffrey W. Pippin, Alice M. Chang, Ronald D. Krofft, Jeffrey H. Miner, Michael R. Vaughan, Stuart J. Shankland,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoAlthough the normal glomerulus comprises four resident cell types, least is known about the parietal epithelial cells (PECs). This comprehensive review addresses the cellular origin of PECs, discusses the normal structure and protein makeup of PECs, describes PEC function, and defines the responses to injury in disease and how these events lead to clinical events. The data show that PECs have unique properties and that new functions are being recognized such as their role in differentiating into podocytes during disease. Although the normal glomerulus comprises four resident cell types, least is known about the parietal epithelial cells (PECs). This comprehensive review addresses the cellular origin of PECs, discusses the normal structure and protein makeup of PECs, describes PEC function, and defines the responses to injury in disease and how these events lead to clinical events. The data show that PECs have unique properties and that new functions are being recognized such as their role in differentiating into podocytes during disease. Diabetic and non-diabetic glomerular diseases remain the leading causes of chronic and end-stage kidney disease. The glomerulus is a complicated structure comprising two major compartments, the glomerular tuft and the extra-glomerular tuft (Figure 1). Further complexity is underscored by the fact that the glomerulus comprises four resident cell types. Mesangial cells, endothelial cells, and podocytes are within the glomerular tuft, whereas parietal epithelial cells (PECs) comprise the extra-glomerular tuft. These observations beg four major questions. First, from a clinical standpoint, are there diseases specific to each glomerular cell type? Studies have indeed shown that primary injury to each of these cell types is associated with a specific disease. Second, what are the specific functions of each glomerular cell type, and what unique genes make this possible? There is an increasing literature defining the molecular anatomy and biological functions of mesangial cells, endothelial cells, and podocytes. However, comparatively little is known about PECs. Third, how does each cell type respond to injury? Again, although much is known about the cells in the tuft, very little is understood about the PECs, except that they proliferate under certain circumstances. Finally, do the four glomerular cells communicate with one another, and if so, how does this ‘cross-talk’ happen? The overall literature is sparse in this field. Given that major research and clinical strides have been made with mesangial cells, glomerular endothelial cells, and podocytes in the past decade, the PECs are now the ‘poorly understood family member.’ This review is intended to refresh our knowledge of this enigmatic cell, discuss new advances in the field, and challenge clinicians and investigators to invest in clarifying the precise biology and function of PECs in health and disease. To date, we associate many glomerular diseases with primary injury to a specific cell type. For example, thrombotic microangiopathies are associated with injury to glomerular endothelial cells; mesangial proliferative glomerulopathies such as IgA nephropathy is due to mesangial cell injury; and many forms of nephrotic syndromes such as focal segmental glomerulosclerosis (FSGS), minimal change disease, and membranous nephropathy are due to injury of podocytes. What about PECs? To date, it is the authors’ view that there is no conclusive evidence to support a primary form of injury to PECs. We know, however, that PECs are very reactive in many forms of glomerular diseases and even undergo robust proliferation in diseases of the glomerular basement membrane (GBM) (e.g., anti-GBM disease) and diseases of the endothelial cells (e.g., anti-neutrophil cytoplasmic antibody (ANCA) and pauci-immune glomerulonephritis). Many have suggested that PECs proliferate in collapsing forms of FSGS. Yet, in all these diseases, it appears that PECs are responding secondarily to injury elsewhere (GBM, endothelial cells, podocytes). This observation does not minimize their importance by any means, but rather should be viewed as a challenge to unravel the mysteries of this cell, in health and disease. In order to fully understand the role of PECs in health and disease, we must first define its origin. PECs share a common lineage with other epithelial cells of the kidney. The definitive adult kidney of higher vertebrates develops through a series of inductive interactions between the ureteric bud and the surrounding metanephric mesenchyme. The later develops into the renal vesicle, which forms glomeruli and tubules. The presumptive glomerulus passes through distinct and sequential developmental stages called the comma, S-shape, capillary loop, and mature stages.1.Saxen L. Organogenesis of the Kidney. Cambridge University Press, New York1987Crossref Google Scholar The two epithelial cells of the glomerulus, PECs and visceral epithelial cells (podocytes), share a common lineage until the S-shaped stage of glomerulogenesis. Between the S-shaped body and capillary loop stages, each cell begins to express distinct genes, used as ‘cell-specific markers.’ For example, Wilm's tumor suppressor protein 1 (WT-1) expression is no longer detected in PECs, whereas podocytes maintain WT-1 and gain vimentin expression. In mice, PECs express CD10 in the capillary loop stage of development.2.Smeets B. Dijkman H.B. Wetzels J.F. et al.Lessons from studies on focal segmental glomerulosclerosis: an important role for parietal epithelial cells?.J Pathol. 2006; 210: 263-272Crossref PubMed Scopus (32) Google Scholar Thus, mature PECs and podocytes express distinctive cell-type markers that can be used to distinguish them under normal conditions. Mounting evidence suggests certain growth factors have a critical role in PEC development. Crim1, a transmembrane cysteine-rich repeat containing protein that tethers growth factors to the cell surface, is expressed in PECs during kidney development. Crim1 null mice are lethal with glomerular capillary loop dilation.3.Wilkinson L. Gilbert T. Kinna G. et al.Crim1KST264/KST264 mice implicate Crim1 in the regulation of vascular endothelial growth factor-A activity during glomerular vascular development.J Am Soc Nephrol. 2007; 18: 1697-1708Crossref PubMed Scopus (52) Google Scholar Drummond et al.4.Drummond I.A. Mukhopadhyay D. Sukhatme V.P. Expression of fetal kidney growth factors in a kidney tumor line: role of FGF2 in kidney development.Exp Nephrol. 1998; 6: 522-533Crossref PubMed Scopus (23) Google Scholar identified fibroblast growth factor 2 (FGF2) as a potential growth factor important in kidney development, which is expressed in nephron precursors and differentiating PECs. Platelet-derived growth factor D (PDGF-D) is expressed in the comma and S-shaped stages of glomerular development and by podocytes in later stages. However, the receptor for PDGF-D localizes to PECs. The proximity between PDGF-D expression by podocytes and its receptor on PECs suggests a possible paracrine role for PDGF-D on PEC development.5.Changsirikulchai S. Hudkins K.L. Goodpaster T.A. et al.Platelet-derived growth factor-D expression in developing and mature human kidneys.Kidney Int. 2002; 62: 2043-2054Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Evidence suggests a role for protein kinase C beta II signaling,6.Saxena R. Saksa B.A. Hawkins K.S. et al.Protein kinase C beta I and beta II are differentially expressed in the developing glomerulus.FASEB J. 1994; 8: 646-653PubMed Google Scholar vitamin D,7.Johnson J.A. Grande J.P. Roche P.C. et al.1 alpha, 25-Dihydroxyvitamin D3 receptor ontogenesis in fetal renal development.Am J Physiol. 1995; 269: F419-F428PubMed Google Scholar cytokeratins,7.Johnson J.A. Grande J.P. Roche P.C. et al.1 alpha, 25-Dihydroxyvitamin D3 receptor ontogenesis in fetal renal development.Am J Physiol. 1995; 269: F419-F428PubMed Google Scholar desmosomal antigens,8.Garrod D.R. Fleming S. Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos.Development. 1990; 108: 313-321PubMed Google Scholar and vimentin9.Nagata M. Yamaguchi Y. Ito K. Loss of mitotic activity and the expression of vimentin in glomerular epithelial cells of developing human kidneys.Anat Embryol (Berl). 1993; 187: 275-279Crossref PubMed Scopus (86) Google Scholar in PEC development. These studies provide important information in our understanding of PEC development, but further studies of these and other potential regulators are necessary to gain a more complete understanding of PEC development and differentiation. Although the border surrounding the urinary space of the glomerulus is commonly referred to as Bowman's capsule, it is more accurate to refer to this structure as Bowman's basement membrane (BBM) lined by a monolayer of PECs, which resemble squamous epithelial cells, with a small cell body size ranging in thickness from 0.1 to 0.3 micro m, increasing to 2.0–3.5 micro m at the nucleus.10.Brenner B.M. Brenner and Rector's The Kidney. 8th edn. W.B. Saunders, Philadelphia2008Google Scholar Scanning electron microscopic studies show that PEC surfaces are lined by the microvilli and cilia.11.Arakawa M. Tokunaga J. A scanning electron microscope study of the human Bowman's epithelium.Contrib Nephrol. 1977; 6: 73-78Crossref PubMed Google Scholar Interestingly, there is variation in the presence of microvilli and cilia, as not all PECs have microvilli; the number of cilia range from 0 to 2 per cell (Figure 2).11.Arakawa M. Tokunaga J. A scanning electron microscope study of the human Bowman's epithelium.Contrib Nephrol. 1977; 6: 73-78Crossref PubMed Google Scholar The number of PECs in a normal rat glomerulus is estimated to comprise 14.8% of all glomerular cells.12.Bertram J.F. Soosaipillai M.C. Ricardo S.D. et al.Total numbers of glomeruli and individual glomerular cell types in the normal rat kidney.Cell Tissue Res. 1992; 270: 37-45Crossref PubMed Scopus (113) Google Scholar Despite their thin cell bodies, PECs form junctions between adjacent cells, comprising a very complicated and delicate structure, described as ‘labyrinth-like.’ Transmission electron microscopic studies show tight junctions near the apical surface of PECs (Figure 3). The proteins expressed in PEC tight junctions are described below. At the urinary pole of the glomerulus, PECs form junctions with proximal tubular cells (Figure 4). At the vascular pole of the glomerulus, PECs transition with podocytes. Indeed, Gibson et al.13.Gibson I.W. Downie I. Downie T.T. et al.The parietal podocyte: a study of the vascular pole of the human glomerulus.Kidney Int. 1992; 41: 211-214Abstract Full Text PDF PubMed Scopus (42) Google Scholar noted that podocytes in this region are often located on BBM in human glomeruli. Moreover, podocytes on BBM form foot processes and slit diaphragms (Figure 5), just as they do when situated on the GBM. Accordingly, the authors named this subset of cells ‘parietal podocytes,’ (pPods) and now are often referred to as pPod. They are present in 63% of glomeruli in normal human kidneys by scanning electron microscopy. Furthermore, pPods form a bridge between BBM and the GBM (Figure 5).13.Gibson I.W. Downie I. Downie T.T. et al.The parietal podocyte: a study of the vascular pole of the human glomerulus.Kidney Int. 1992; 41: 211-214Abstract Full Text PDF PubMed Scopus (42) Google Scholar Although pPods were described ultrastructurally by Gibson, Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar recently noted that pPods express several proteins considered specific to podocytes (discussed below). Following these reports, the concept of the pPod has now become more widely accepted, although their origin and function has yet to be determined.Figure 5Transmission electron microscopic image of the vascular pole of the glomerulus showing a bridging parietal podocyte (BPP) and foot processes formed on both the glomerular basement membrane (GBM) and Bowman's basement membrane (BBM) sides of the parietal podocyte. Bridging parietal podocytes often bridge the GBM and the BBM, as shown here. Reprinted with permission from Gibson et al.13.Gibson I.W. Downie I. Downie T.T. et al.The parietal podocyte: a study of the vascular pole of the human glomerulus.Kidney Int. 1992; 41: 211-214Abstract Full Text PDF PubMed Scopus (42) Google Scholar A, arteriole of vascular pole; C, pericapsular capillary; CL, capillary loop.View Large Image Figure ViewerDownload (PPT) PECs and pPods at not the only cells lining BBM. Another distinct glomerular cell located at the vascular pole was reported by Ryan et al.,15.Ryan G.B. Coghlan J.P. Scoggins B.A. The granulated peripolar epithelial cell: a potential secretory component of the renal juxtaglomerular complex.Nature. 1979; 277: 655-656Crossref PubMed Scopus (56) Google Scholar called the peripolar cell (Figure 6). Peripolar cells are characterized by their localization at the vascular pole on BBM, between podocytes and PECs. Their cytoplasm is periodic acid Schiff-positive and contains large electron-dense granules (Figure 7). Newborn lambs have a prominent number of peripolar cells with a large number of granules, containing albumin, immunoglobulin, neuron-specific enolase, and transthyretin.16.Alcorn D. Ryan G.B. The glomerular peripolar cell.Kidney Int Suppl. 1993; 42: S35-S39PubMed Google Scholar,17.Gardiner D.S. Downie I. Gibson I.W. et al.The glomerular peripolar cell: a review.Histol Histopathol. 1991; 6: 567-573PubMed Google Scholar Peripolar cell cytoplasm also contains renin, suggesting, although not proving, that peripolar cells may be involved in the control of blood flow into the glomerulus.Figure 7Transmission electron microscopic image of a peripolar cell with periodic acid Schiff–positive electron-dense granules contained within the cytoplasm. Reprinted with permission of Gardiner et al.17.Gardiner D.S. Downie I. Gibson I.W. et al.The glomerular peripolar cell: a review.Histol Histopathol. 1991; 6: 567-573PubMed Google Scholar er, endoplasmic reticulum; m, mitochondria.View Large Image Figure ViewerDownload (PPT) A discussion of PECs cannot be complete without acknowledging BBM, given that PECs are adherent to this membrane. BBM is an especially thick basement membrane that differs in composition from the GBM with which it is contiguous. BBM is presumably synthesized exclusively by PECs, although this has not yet been definitively proven. Like all basement membranes, BBM contains laminin, collagen IV, nidogen, and heparan sulfate proteoglycans. Data in the literature indicate that specific isoforms of some of these matrix protein classes are present. The major laminins deposited into BBM include both laminin-111 (α1β1γ1) and laminin-511 (α5β1γ1).18.Miner J.H. Patton B.L. Lentz S.I. et al.The laminin alpha chains: expression, developmental transitions, and chromosomal locations of alpha1-5, identification of heterotrimeric laminins 8-11, and cloning of a novel alpha3 isoform.J Cell Biol. 1997; 137: 685-701Crossref PubMed Scopus (565) Google Scholar,19.Sorokin L.M. Pausch F. Durbeej M. et al.Differential expression of five laminin alpha (1–5) chains in developing and adult mouse kidney.Dev Dyn. 1997; 210: 446-462Crossref PubMed Scopus (135) Google Scholar Regarding collagen IV, the major networks appear to be collagen α1,α2(IV) and collagen α5,α6(IV), although the α3(IV) chain has also been observed.20.Kang J.S. Wang X.P. Miner J.H. et al.Loss of alpha3/alpha4(IV) collagen from the glomerular basement membrane induces a strain-dependent isoform switch to alpha5alpha6(IV) collagen associated with longer renal survival in Col4a3-/- Alport mice.J Am Soc Nephrol. 2006; 17: 1962-1969Crossref PubMed Scopus (47) Google Scholar,21.Ninomiya Y. Kagawa M. Iyama K. et al.Differential expression of two basement membrane collagen genes, COL4A6 and COL4A5, demonstrated by immunofluorescence staining using peptide-specific monoclonal antibodies.J Cell Biol. 1995; 130: 1219-1229Crossref PubMed Scopus (250) Google Scholar The presence of α5 and α6(IV) distinguishes BBM from the GBM, which lacks α6(IV). Despite the prominence of COL4A5, which is mutated or missing in most cases of Alport syndrome, there are no reported BBM-specific defects associated with this disease. Both nidogens-1 and -2 are present in BBM and likely contribute to its stability by binding both laminin and collagen IV.22.Willem M. Miosge N. Halfter W. et al.Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development.Development. 2002; 129: 2711-2722PubMed Google Scholar Regarding heparan sulfate proteoglycans in BBM, both perlecan and collagen XVIII are present,23.Erickson A.C. Couchman J.R. Basement membrane and interstitial proteoglycans produced by MDCK cells correspond to those expressed in the kidney cortex.Matrix Biol. 2001; 19: 769-778Crossref PubMed Scopus (28) Google Scholar although their functions have not yet been identified. Clearly, further study of the BBM is needed. Recent studies have shown that many renal cell types express unique genes, which serve not only as a ‘marker’ for identification specificity on a biopsy but likely also serve cell-type-specific functions. Several excellent reviews discuss podocyte-specific proteins in health and disease. Several proteins expressed by PECs have also recently been described, and these are listed in Table 1. We have listed PEC proteins based on their potential functional classification:Table 1Proteins expressed in PECs, podo, and pPodCategoryProteinPECPodocytepPodReferenceTranscription factor (PEC)PAX2+++-+Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)PAX8+++-+Ohse et al.28.Ohse T, Chang A, Pippin J et al. A new function for parietal epithelial cells: a second glomerular barrier (accepted).Google ScholarHNF1b+-NAIgarashi30.Igarashi P. Following the expression of a kidney-specific gene from early development to adulthood.Nephron Exp Nephrol. 2003; 94: e1-e6Crossref PubMed Scopus (11) Google ScholarTight junctionClaudin-1+-+Kiuchi-Saishin et al.24.Kiuchi-Saishin Y. Gotoh S. Furuse M. et al.Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments.J Am Soc Nephrol. 2002; 13: 875-886Crossref PubMed Google Scholar and Ohse et al.26.Ohse T. Pippin J.W. Vaughan M.R. et al.Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture.J Am Soc Nephrol. 2008; 19: 1879-1890Crossref PubMed Scopus (64) Google ScholarClaudin-2+-NAKiuchi-Saishin et al.24.Kiuchi-Saishin Y. Gotoh S. Furuse M. et al.Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments.J Am Soc Nephrol. 2002; 13: 875-886Crossref PubMed Google Scholar and Ohse et al.26.Ohse T. Pippin J.W. Vaughan M.R. et al.Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture.J Am Soc Nephrol. 2008; 19: 1879-1890Crossref PubMed Scopus (64) Google ScholarClaudin-3++NADone et al.25.Done S.C. Takemoto M. He L. et al.Nephrin is involved in podocyte maturation but not survival during glomerular development.Kidney Int. 2008; 73: 697-704Abstract Full Text Full Text PDF PubMed Scopus (41) Google ScholarOccludin+-NAOhse et al.28.Ohse T, Chang A, Pippin J et al. A new function for parietal epithelial cells: a second glomerular barrier (accepted).Google ScholarZO-1++NASchnabel et al.27.Schnabel E. Anderson J.M. Farquhar M.G. The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium.J Cell Biol. 1990; 111: 1255-1263Crossref PubMed Scopus (243) Google Scholar and Ohse et al.28.Ohse T, Chang A, Pippin J et al. A new function for parietal epithelial cells: a second glomerular barrier (accepted).Google ScholarOther junctionK-cadherin+-NACho et al.29.Cho E.A. Patterson L.T. Brookhiser W.T. et al.Differential expression and function of cadherin-6 during renal epithelium development.Development. 1998; 125: 803-812PubMed Google ScholarKSP-cadherin+-NAIgarashi30.Igarashi P. Following the expression of a kidney-specific gene from early development to adulthood.Nephron Exp Nephrol. 2003; 94: e1-e6Crossref PubMed Scopus (11) Google ScholarEnzymePGP9.5+-NAShirato et al.35.Shirato I. Asanuma K. Takeda Y. et al.Protein gene product 9.5 is selectively localized in parietal epithelial cells of Bowman's capsule in the rat kidney.J Am Soc Nephrol. 2000; 11: 2381-2386PubMed Google Scholar (rt)Diomedi-Camassei et al.36.Diomedi-Camassei F. Rava L. Lerut E. et al.Protein gene product 9.5 and ubiquitin are expressed in metabolically active epithelial cells of normal and pathologic human kidney.Nephrol Dial Transplant. 2005; 20: 2714-2719Crossref PubMed Scopus (21) Google Scholar (h)Ohse et al.26.Ohse T. Pippin J.W. Vaughan M.R. et al.Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture.J Am Soc Nephrol. 2008; 19: 1879-1890Crossref PubMed Scopus (64) Google Scholar (m)CD10++ (human)NASmeets et al.32.Smeets B. Te Loeke N.A. Dijkman H.B. et al.The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.J Am Soc Nephrol. 2004; 15: 928-939Crossref PubMed Scopus (68) Google Scholar (m)Dijkman et al.31.Dijkman H.B. Weening J.J. Smeets B. et al.Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.Kidney Int. 2006; 70: 338-344Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and Debiec et al.33.Debiec H. Guigonis V. Mougenot B. et al.Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies.N Engl J Med. 2002; 346: 2053-2060Crossref PubMed Scopus (378) Google Scholar (h, rab)AntioxidantCeruloplasmin+-NAWiggins et al.37.Wiggins J.E. Goyal M. Wharram B.L. et al.Antioxidant ceruloplasmin is expressed by glomerular parietal epithelial cells and secreted into urine in association with glomerular aging and high-calorie diet.J Am Soc Nephrol. 2006; 17: 1382-1387Crossref PubMed Scopus (30) Google Scholar (rt)Intermediate filamentCytokeratin (mAb C2562)+--Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Cytokeratin 8+-NADijkman et al.31.Dijkman H.B. Weening J.J. Smeets B. et al.Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.Kidney Int. 2006; 70: 338-344Abstract Full Text Full Text PDF PubMed Scopus (92) Google ScholarDesmin-+NAStamenkovic et al.39.Stamenkovic I. Skalli O. Gabbiani G. Distribution of intermediate filament proteins in normal and diseased human glomeruli.Am J Pathol. 1986; 125: 465-475PubMed Google ScholarVimentin-+NAStamenkovic et al.39.Stamenkovic I. Skalli O. Gabbiani G. Distribution of intermediate filament proteins in normal and diseased human glomeruli.Am J Pathol. 1986; 125: 465-475PubMed Google ScholarGlycoproteinPodocalyxin-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Transcription factor (podocyte)WT-1-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Slit diaphragmNephrin-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Podocin-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Actin-associatedα-ACTN4-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Synaptopodin-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Tyrosine phosphataseGLEPP-1-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Cell cycleCKIp57-+±Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)Growth factorVEGF-++Bariety et al.14.Bariety J. Mandet C. Hill G.S. et al.Parietal podocytes in normal human glomeruli.J Am Soc Nephrol. 2006; 17: 2770-2780Crossref PubMed Scopus (119) Google Scholar (h)ACTN-4, actinin; GLEPP, glomerular epithelial protein; h, human; HNF1b, hepatocyte nuclear factor; KSP, kidney specific; m, mouse; mAb, monoclonal antibody; NA, not applicable; PAX, paired box gene 2; PEC, parietal epithelial cell; PGP9.5, protein gene product 9.5; Ppod, parietal podocyte; rt, rat; VEGF, vascular endothelial growth factor; WT-1, Wilm's tumor suppressor protein 1; ZO-1, zonula occludens-1. Open table in a new tab ACTN-4, actinin; GLEPP, glomerular epithelial protein; h, human; HNF1b, hepatocyte nuclear factor; KSP, kidney specific; m, mouse; mAb, monoclonal antibody; NA, not applicable; PAX, paired box gene 2; PEC, parietal epithelial cell; PGP9.5, protein gene product 9.5; Ppod, parietal podocyte; rt, rat; VEGF, vascular endothelial growth factor; WT-1, Wilm's tumor suppressor protein 1; ZO-1, zonula occludens-1. Parietal epithelial cells contain junctional structures, including several tight junction proteins and cadherins. Claudins form a major component of tight junctions. Of the claudins expressed in mouse kidneys, claudin-1, -2 and -3 are expressed in PECs.24.Kiuchi-Saishin Y. Gotoh S. Furuse M. et al.Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments.J Am Soc Nephrol. 2002; 13: 875-886Crossref PubMed Google Scholar, 25.Done S.C. Takemoto M. He L. et al.Nephrin is involved in podocyte maturation but not survival during glomerular development.Kidney Int. 2008; 73: 697-704Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 26.Ohse T. Pippin J.W. Vaughan M.R. et al.Establishment of conditionally immortalized mouse glomerular parietal epithelial cells in culture.J Am Soc Nephrol. 2008; 19: 1879-1890Crossref PubMed Scopus (64) Google Scholar Zonula occludens-1 (ZO-1) expression has been shown in PECs by immunofluorescent staining and immunogold electron microscopy.27.Schnabel E. Anderson J.M. Farquhar M.G. The tight junction protein ZO-1 is concentrated along slit diaphragms of the glomerular epithelium.J Cell Biol. 1990; 111: 1255-1263Crossref PubMed Scopus (243) Google Scholar We recently confirmed the expression of ZO-1 and occludin in PECs in mouse, rat, and humans.28.Ohse T, Chang A, Pippin J et al. A new function for parietal epithelial cells: a second glomerular barrier (accepted).Google Scholar The expression pattern of these tight junction proteins was consistent with junctional structures. At least two cadherins are expressed in PECs: K-cadherin (Cdh6)29.Cho E.A. Patterson L.T. Brookhiser W.T. et al.Differential expression and function of cadherin-6 during renal epithelium development.Development. 1998; 125: 803-812PubMed Google Scholar and kidney specific-cadherin (Cdh16).30.Igarashi P. Following the expression of a kidney-specific gene from early development to adulthood.Nephron Exp Nephrol. 2003; 94: e1-e6Crossref PubMed Scopus (11) Google Scholar Igarashi30.Igarashi P. Following the expression of a kidney-specific gene from early development to adulthood.Nephron Exp Nephrol. 2003; 94: e1-e6Crossref PubMed Scopus (11) Google Scholar reported that the transcription factor HNF1b, which regulates kidney specific-cadherin, is expressed in PECs. Another transcription factor from the paired box family, PAX2 is exclusively expressed within the glomerulus in PECs.31.Dijkman H.B. Weening J.J. Smeets B. et al.Proliferating cells in HIV and pamidronate-associated collapsing focal segmental glomerulosclerosis are parietal epithelial cells.Kidney Int. 2006; 70: 338-344Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar PAX2 is involved in regulating genes governing proliferation, cell growth, and survival, and interestingly has reciprocal expression levels with the transcription factor WT-1 in podocytes. We have recently shown that within the glomerulus, another member of the paired box gene family, PAX8 was also exclusively expressed in PECs.28.Ohse T, Chang A, Pippin J et al. A new function for parietal epithelial cells: a second glomerular barrier (accepted).Google Scholar CD10, also known as CALLA or neutral endopeptidase, has been used to detect PECs in an experimental model in mice.32.Smeets B. Te Loeke N.A. Dijkman H.B. et al.The parietal epithelial cell: a key player in the pathogenesis of focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.J Am Soc Nephrol. 2004; 15: 928-939Crossref PubMed Scopus (68) Google Scholar Interestingl
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